DESCRIPTION (provided by investigator): A large body of experimental data indicates that vitamin D inhibits cellular proliferation and induces differentiation and apoptosis, suggesting a protective effect against cancer. The enzymes coding for the formation and degradation of 1,25(OH)2D, the active metabolite of vitamin D, are present in both normal and cancer breast cells, as is the vitamin D receptor, a key mediator in the vitamin D pathway. Ecological and case- control studies support a protective role of vitamin D against breast cancer; however, prospective data are sparse. Moreover, few studies have measured circulating 25(OH)D which is considered the best indicator of vitamin D status because it captures both the absorption of vitamin D in the intestine and its production in the skin. We propose to conduct a comprehensive study of the vitamin D pathway in relation to breast cancer risk. Because vitamin D impacts cell proliferation, the main mechanism by which estrogens increase breast cancer risk, we will also assess whether vitamin D modifies the association of circulating estradiol with breast cancer risk in postmenopausal women. The study will be a case-control study nested within two cohorts, the NYU Women's Health Study and the Mammary Screening Cohort in Sweden. These two cohorts have a similar design and collected biological samples prospectively. A total of 1,995 incident cases is expected to be observed within these two cohorts. One (or two for cases d 52 years of age) control(s) will be selected for each case, matching the case on cohort, race/ethnicity, menopausal status, age at, and date of, blood donation. In addition to baseline measurements, we will assess 25(OH)D at repeat points in time in about 50 percent of the matched sets (2 samples in 25 percent and 3 samples in 25 percent). We will also assess genetic variation in vitamin D-related genes (CYP27A1, CYP24A1, DBP, VDR, and RXRA) and evaluate the joint effects of circulating 25(OH)D and variants in these genes on breast cancer risk. Circulating levels of estradiol will be measured in postmenopausal matched sets. PUBLIC HEALTH RELEVANCE: Breast cancer is the cancer with highest incidence in women in the US. Most of the known risk factors for breast cancer (genetic and reproductive) are not readily modifiable. By contrast, if vitamin D proves to be protective against breast cancer, levels are readily modifiable through supplements which are nontoxic and inexpensive. Since a significant fraction of the American population has suboptimal levels of vitamin D, there would be a large potential for breast cancer prevention.